Specific MHC class II molecules are linked to the susceptibility to autoimmune diseases in humans and experimental animals. The MHC class II molecules HLA-DQ8 and HLA-DQ2 in humans and I-Ag7 in NOD mice, for example, appear to confer susceptibility to type I diabetes. The specificity of these molecules is found in their peptide binding sites. The three-dimensional structures of MHC class II complexes with peptides from candidate auto antigens could provide a description of the atomic interactions specific to the high-risk class II molecules. A detailed understanding of the specificity of these MHC molecules should provide a background for helping to discover antigenic epitopes from candidate autoantigens and guide the design of selective blockers of these MHC class II molecules. The synthesis of specific blockers would allow the mechanisms by which these MHC molecules cause susceptibility to be examined in the initiation and progression of disease. The specific aims of this proposal are: 1) to express soluble, human MHC class II molecules (HLA-DQ8, HLA-DQ2) conferring susceptibility to diabetes and to load them with peptides from candidate autoantigens, 2) to crystallize HLA-DQ8 and HLA-DQ2 complexed with peptides and determine their three-dimensional structures by X-ray crystallography, 3) to use structural information to design both specific ligands and libraries of non-peptidic ligands of the peptide binding site of MHC class II molecules conferring susceptibility to diabetes, 4) to assay these compounds for their ability to bind to their class II receptor, and 5) to examine the effect of selective blockers on the development of autoaggressive T cells and on the progression of disease in NOD mice transgenic for DQ8 or DQ2 susceptibility genes.